Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ex vivo generated human T-lymphoid progenitors as a tool to accelerate immune reconstitution after partially HLA compatible hematopoietic stem cell transplantation or after gene therapy

A Correction to this article was published on 16 March 2022

This article has been updated

Abstract

Prolonged T-cell immunodeficiency following HLA- incompatible hematopoietic stem cell transplantation (HSCT) represents a major obstacle hampering the more widespread use of this approach. Strategies to fasten T-cell reconstitution in this setting are highly warranted as opportunistic infections and an increased risk of relapse account for high rates of morbidity and mortality especially during early month following this type of HSCT. We have implemented a feeder free cell system based on the use of the notch ligand DL4 and cytokines allowing for the in vitro differentiation of human T-Lymphoid Progenitor cells (HTLPs) from various sources of CD34+ hematopoietic stem and precursor cells (HSPCs). Co- transplantion of human T-lymphoid progenitors (HTLPs) and non- manipulated HSPCs into immunodeficient mice successfully accelerated the reconstitution of a polyclonal T-cell repertoire. This review summarizes preclinical data on the use of T-cell progenitors for treatment of post- transplantation immunodeficiency and gives insights into the development of GMP based protocols for potential clinical applications including gene therapy approaches. Future clinical trials implementing this protocol will aim at the acceleration of immune reconstitution in different clinical settings such as SCID and leukemia patients undergoing allogeneic transplantation. Apart from pure cell-therapy approaches, the combination of DL-4 culture with gene transduction protocols will open new perspectives in terms of gene therapy applications for primary immunodeficiencies.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1

Change history

References

  1. Reisner Y, Itzicovitch LEA, Meshorer A, Sharon N. Hemopoietic stem cell transplant using mouse bone marrow spleen cells fractionated lectins. Proc Natl Acad Sci USA. 1978;75:2933–6.

  2. Urbano-Ispizua A, Rozman C, Martínez C, Marín P, Briones J, Rovira M, et al. Rapid engraftment without significant graft-versus-host disease after allogeneic transplantation of CD34 + selected cells from peripheral blood. Blood. 1997;89:3967–73.

    CAS  Article  Google Scholar 

  3. Robinson TM, O’Donnell PV, Fuchs EJ,  Luznik L. Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol 2016;53:90–7.

    Article  Google Scholar 

  4. Toubert A, Glauzy S, Douay C, Clave E. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: Never say never again. Tissue Antigens. 2012;79:83–9.

    CAS  Article  Google Scholar 

  5. Williams KM, Hakim FT, Gress RE. T cell immune reconstitution following lymphodepletion. Semin Immunol 2007;19:318–30.

    CAS  Article  Google Scholar 

  6. Krenger W, Blazar BR, Hollander GA. Review article Thymic T-cell development in allogeneic stem cell transplant. Blood 2011;117:6768–76.

  7. Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, et al. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: A PIDTC natural history study. Blood. 2017;130:2718–27.

    CAS  Article  Google Scholar 

  8. Touzot F, Moshous D, Creidy R, Neven B, Frange P, Cros G, et al. Faster T-cell development following gene therapy compared to haplo-identical hematopoietic stem cell transplantation in the treatment of SCID-X1. Blood. 2015;125:1–8.

    Article  Google Scholar 

  9. Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol 2008;30:425–37.

    Article  Google Scholar 

  10. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol 2012;19:324–55.

    Article  Google Scholar 

  11. Reimann C, Dal Cortivo L, Hacein-Bey-Abina S, Fischer A, André-Schmutz I, Cavazzana-Calvo M. Advances in adoptive immunotherapy to accelerate T-cellular immune reconstitution after HLA-incompatible hematopoietic stem cell transplantation. Immunotherapy. 2010;2:481–96.

    CAS  Article  Google Scholar 

  12. Clave E, Lisini D, Douay C, Giorgiani G, Busson M, Zecca M, et al. Thymic function recovery after unrelated donor cord blood or T-cell depleted HLA-haploidentical stem cell transplantation correlates with leukemia relapse. Front Immunol 2013;4:1–8.

    CAS  Article  Google Scholar 

  13. Cavazzana M, Six E, Lagresle-Peyrou C, André-Schmutz I, Hacein-Bey-Abina S. Gene therapy for X-linked severe combined immunodeficiency: where do we stand? Hum Gene Ther 2016;27:108–16.

    CAS  Article  Google Scholar 

  14. Hazenberg MD1, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D, et al. T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. 2002;99:3449–53.

  15. Clave E, Busson M, Douay C, Peffault de Latour R, Berrou J, Rabian C, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood. 2011;113:6477–84.

  16. Chaudhry MS, Velardi E, Malard F, van den Brink MR. Immune reconstitution after allogeneic hematopoietic stem cell transplantation: time to T up the thymus. J Immunol 2017;198:40–6.

    CAS  Article  Google Scholar 

  17. Krenger W, Rossi S, Holländer GA. Apoptosis of thymocytes during acute graft-versus-host disease is independent of glucocorticoids. Transplantation. 2000;69:2190–3.

    CAS  Article  Google Scholar 

  18. Wang SD, Huang KJ, Lin YS, Lei HY. Sepsis-induced apoptosis of the thymocytes in mice. J Immunol. 1994;152:5014–21.

    CAS  PubMed  Google Scholar 

  19. Hick RW, Gruver AL, Ventevogel MS, Haynes BF, Sempowski GD. Leptin selectively augments thymopoiesis in leptin deficiency and lipopolysaccharide-induced thymic atrophy. J Immunol 2006;177:169–76.

    CAS  Article  Google Scholar 

  20. Mocarski ES, Bonyhadif M, Salimif S, McCune JM, Kaneshima H. Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication. Med Sci 1993;90:104–8.

    CAS  Google Scholar 

  21. Koning C, de, Admiraal R, Nierkens S, Boelens JJ. Human herpesvirus 6 viremia affects T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Blood Adv 2018;2:428–32.

    CAS  Article  Google Scholar 

  22. Svaldi M, Lanthaler AJ, Dugas M, Lohse P, Pescosta N, Straka C, et al. T-cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients. Br J Haematol 2003;122:795–801.

    CAS  Article  Google Scholar 

  23. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, Pierres M, et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 2008;205:2515–23.

    CAS  Article  Google Scholar 

  24. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, Ando K, et al. Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 2008;205:2507–13.

    CAS  Article  Google Scholar 

  25. Taghon T, Waegemans E, Van de Walle I. Notch signaling during human T cell development. Curr Top Microbiol Immunol. 2012;360:75–97.

  26. Hosokawa H, Rothenberg EV. Cytokines, Transcription Factors, and the Initiation of T-cell development. Cold Spring Harb Perspect Biol. 2018;1:1–20.

  27. Six EM, Benjelloun F, Garrigue A,  Bonhomme D, Morillon E, Rouiller J, et al. Cytokines and culture medium have a major impact on human in vitro T-cell differentiation. Blood Cells Mol Dis 2011;47:72–8.

    CAS  Article  Google Scholar 

  28. Schmitt TM, Zúñiga-Pflücker JC. Thymus-derived signals regulate early T-cell development. Crit Rev Immunol 2005;25:141–59.

    CAS  Article  Google Scholar 

  29. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 2010;16:232–6.

    CAS  Article  Google Scholar 

  30. Reimann C, Six E, Dal-Cortivo L, Schiavo A, Appourchaux K, Lagresle-Peyrou C,  et al. Human T-lymphoid progenitors generated in a feeder-cell-free delta-like-4 culture system promote T-cell reconstitution in NOD/SCID/γc-/-mice. Stem Cells. 2012;30:1771–80.

    CAS  Article  Google Scholar 

  31. Six EM, Bonhomme D, Monteiro M, Beldjord K, Jurkowska M, Cordier-Garcia C, et al. A human postnatal lymphoid progenitor capable of circulating and seeding the thymus. J Exp Med 2007;204:3085–93.

    CAS  Article  Google Scholar 

  32. Simons L, Ma K, de Chappedelaine C, Elkaim E, Olivré J, Susini S, et al. Generation of adult human T-cell progenitors for immunotherapeutic applications. J Allergy Clin Immunol 2018;141:1491–1494.e4.

    CAS  Article  Google Scholar 

  33. Hacein-Bey-Abina S, Pai S-Y, Gaspar HB, Armant M, Berry CC, Blanche S, et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 2014;371:1407–17.

    Article  Google Scholar 

  34. Bernadin O, Amirache F, Girard-Gagnepain A, Moirangthem RD, Lévy C, Ma K et al. Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency. Blood Adv. 2019;3:461–75.

Download references

Acknowledgements

We thank Pauline Huguenin for help in bibliography.

Funding

The study was funded by the French National Institute of Health and Medical Research (INSERM), a European Research Council grant (ERC Regenerative Therapy, 269037), a European Union FP7 grant (CELL-PID, 261387), a European Union H2020 grant (SCIDNet, 666908), Imagine Institute, a Clinical Research Hospital Program (PHRC) (Ministry of Health and Social Affairs), an INCA-Plan Cancer grant (2009–2013) and a public grant overseen by the French National Research Agency (ANR) as part of the program “Investissements d’Avenir” (reference: ANR-10-IAHU-01). LS was funded by Imagine Institute. KM was funded by a China Scholarship Council (CSC). EE was funded by an INSERM-Plan Cancer fellowship. CR was funded by postdoctoral scholarships from the Deutsche Forschungsgemeinschaft (DFG). TT was funded by the Fund for Scientific Research Flanders (FWO Vlaanderen research projects G0B2913N). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isabelle André.

Ethics declarations

Conflict of interest

MC and IA-S own equity in Smart Immune and hold two patents in this area, about the in vitro process of production of T-cell progenitors. KM is co-inventor of patent WO 2018/146297 A1, Methods for generating T-cells progenitors. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

André, I., Simons, L., Ma, K. et al. Ex vivo generated human T-lymphoid progenitors as a tool to accelerate immune reconstitution after partially HLA compatible hematopoietic stem cell transplantation or after gene therapy. Bone Marrow Transplant 54, 749–755 (2019). https://doi.org/10.1038/s41409-019-0599-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-019-0599-9

Search

Quick links